Research progress over the last four years, made under the auspices of the Program Project and independently by other investigators, has both supported our hypothesis and added great detail. Work supported by this inflammation in animal models and human disease. This very productive Program Project grant, entitled, """"""""IBD: Genetic and Immunopathologic Mechanisms"""""""" is designed to approach the subject of inflammatory bowel disease from numerous vantage-points. Project 1, """"""""Quantitative Linkage of Crohn's Disease Antibodies"""""""" has made major contributions to the understanding of the genetic susceptibility of IBD. Project 2, """"""""IBD: Disease Subgroup Stratification by Immune Response to Commensal Bacterial Antigens"""""""" has made major contributions to current knowledge of disease stratification, and with Project 3, """"""""Immune Mechanisms of Pathogenesis and Protection for Crohn's Disease (CD) Candidate Microbial Antigens,"""""""" contributed to further understanding of marker antibodies of marker antibodies and relationship to bacterial antigens and T cell responses. Project 3 has also defined a unique CD associated antigen and shown disease associated cytokine responses in CD-like mouse models. Project 4, """"""""Specificity of Homing of Pathogenic T cells in Mouse Colitis,"""""""" has made important observations of the interplay of effector and regulatory T cells in mucosal inflammation. Our efforts have led us to a revised hypothesis guiding the Program Project renewal application as follows: Several genetic abnormalities affect the balance of T cell responses to commensal bacterial antigens. Disease susceptibility arises from an unfavorable genetic profile resulting in an imbalance of antigen specific effector or regulatory cells. These disordered T cell responses are associated with marker serum antibodies with cognate antigen specificity and isotype, and distinct patterns of mucosal damage resulting in the clinical manifestations of ulcerative colitis (UC) and CD. An important medical implication of this imbalance by inhibition of specific cytokines, augmentation of regulatory T cell function, or altering the bacterial microenvironment. The proposed hypothesis will be tested through an integrated set of human and animal model investigations in a highly interactive Program Project. The synergism between research in animal models and in human disease will be accelerated by the interplay of the projects in this Program Project grant. Core B in this proposal will be central and critical for accomplishing the objectives of human and animal studies. If the goals delineated in this proposal are accomplished, we will have a much cleared understanding of the genetic factors and immunologic processes controlling animal and human mucosal inflammation, and the relationship of the mucosal T cell imbalance to marker antibodies and responses to specific bacterial antigens.
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